Coronary flow reserve abnormalities in patients

with diabetes mellitus who have end-stage renal

disease and normal epicardial coronary arteries
Michael Ragosta, MD,a Habib Samady, MD,a Ross B. Isaacs, MD,b Lawrence W. Gimple, MD,a
Ian J. Sarembock, MB, ChB, MD,a and Eric R. Powers, MDa Charlottesville, Va

Background

Diabetic nephropathy is associated with increased cardiovascular events. Coronary atherosclerosis is

responsible for many of these events, but other mechanisms such as impaired flow reserve may be involved. The purpose
of this study was to define the prevalence and mechanism of abnormal coronary velocity reserve (CVR) in patients with
diabetes mellitus who have nephropathy and a normal coronary artery.

Methods

Patients undergoing catheterization for clinical purposes were enrolled. CVR was measured with a Doppler
ultrasound scanning wire in a normal coronary in 32 patients without diabetes mellitus, 11 patients with diabetes mellitus
who did not have renal failure, and 21 patients with diabetes mellitus who had nephropathy. A CVR 2.0 was considered to be abnormal.

Results

Patients with diabetes mellitus who had renal failure had a higher incidence of hypertension and left ventricular hypertrophy. The average peak velocity (APV) at baseline was higher in patients with diabetes mellitus who had renal
failure. At peak hyperemia, APV increased in all 3 groups, with no difference between groups. The mean CVR for patients without diabetes was 2.8 0.8 and was not different from that in patients with diabetes mellitus who did not have
renal failure (2.7 0.7), but was lower than that in patients with diabetes mellitus who had renal failure (1.6 0.5; P
0.001). Abnormal CVR was observed in 9% of patients without diabetes mellitus, 18% of patients with diabetes mellitus
who did not have renal failure, and 57% of patients with diabetes mellitus who had renal failure, and abnormal CVR was
caused by an elevation of baseline APV in 66% of these cases. The baseline heart rate and the presence of diabetes mellitus with renal failure were independent predictors of abnormal CVR by multivariable analysis.

Conclusions Patients with diabetic nephropathy have abnormalities in CVR in the absence of angiographically evident coronary disease. (Am Heart J 2004;147:101723.)

See related Editorial on page 942.

Diabetic nephropathy is associated with cardiovascular events, and cardiovascular complications constitute
the major cause of death in patients with diabetic nephropathy who are awaiting renal transplantation.1 4
Significant research efforts have explored the relationship among diabetes mellitus, renal failure, and atherosclerosis of major epicardial coronary arteries. However, mechanisms other than large vessel atherosclerosis
may be responsible for cardiovascular morbidity and
are not well understood in this population.
From the aCardiovascular Division and bRenal Division, Department of Medicine, University of Virginia Health Systems, Charlottesville, Va.
Submitted December 31, 2002; accepted July 28, 2003.
Reprint requests: Michael Ragosta, MD, Director, Interventional Cardiology, Box
800158, University of Virginia Health Systems, Charlottesville, VA 22908-0158.
E-mail: mragosta@virginia.edu
0002-8703/$ - see front matter
2004, Elsevier Inc. All rights reserved.
doi:10.1016/j.ahj.2003.07.029

Abnormalities in myocardial blood flow and in coronary flow reserve have been observed in both patients
with insulin-treated diabetes mellitus and patients with
non-insulintreated diabetes mellitus with angiographically normal coronary arteries, which suggests the
presence of microvascular disease.57 Because diabetic
nephropathy is associated with microvascular disease
in the kidney, these abnormalities might be particularly evident in patients with end-stage renal disease
(ESRD) as a sequelae of diabetes mellitus.8,9 Whether
the microvascular changes observed in the kidney are
associated with myocardial blood flow abnormalities is
not known.
In the absence of overt coronary artery disease, abnormalities in coronary flow reserve (CFR) and myocardial blood flow may be explained by mechanisms
other than microvascular disease. These include the
presence of unappreciated, diffuse atherosclerosis or
the presence of associated conditions known to impair
CFR, such as hypertensive heart disease, heart failure,
or ventricular hypertrophy. Such conditions are very

American Heart Journal

June 2004

1018 Ragosta et al

Table I. Patient characteristics

Group 1, Group 2, Group 3,
nondiabetic DM no RF DM with RF
No.
Age
Male (%)
Tobacco (%)
Dyslipidemia (%)
Hematocrit (%)
Noncritical CAD (%)
HTN (%)
LVH (%)
Insulin use (%)
Dialysis (%)

32
52 9
17 (53)
17 (53)
26 (81)
39 4
23 (72)
19 (59)
1 (3)
0
0

11
52 11
6 (55)
4 (36)
9 (82)
40 3
7 (64)
4 (36)
0
2 (20)
0

21
52 10
11 (52)
6 (29)
13 (62)
36 6
8 (38)
19 (90)
9 (43)
18 (86)
16 (76)

.99
.55
.16
.43
.03
.02
.03
.002
.002
.001

DM, Diabetes mellitus, RF, renal failure; CAD, coronary artery disease; HTN, hypertension; LVH, left ventricular hypertrophy.

common in patients with renal failure from diabetic

nephropathy. Thus, the purpose of this study was to
define the prevalence and mechanism of abnormal coronary velocity reserve (CVR) in patients with diabetes
mellitus who had nephropathy and an angiographically
normal coronary artery.

Methods
Patient inclusion
The Human Investigations Committee approved the protocol, and all patients gave informed consent. Patients with an
ejection fraction 50% who were referred for coronary angiography with at least 1 major coronary artery appearing
normal were enrolled. An artery was defined as normal
when it appeared smooth, with no lumen irregularities. Noncritical stenoses, defined as lesions with 50% lumen narrowing, in other coronaries were permitted. Patients with
conditions known to impair CFR (valvular heart disease, congestive heart failure, cardiomyopathy, prior intervention on
the artery, past history of myocardial infarction in the territory of the normal artery) and patients who would likely not
tolerate adenosine infusion (hemodynamic instability, presence of a 50% stenosis in another artery, or contraindication to adenosine) were excluded.
In 31 months, 64 patients were enrolled and divided in 3
groups. Group 1 (n 32) included patients without diabetes
mellitus or renal failure. Group 2 (n 11) included patients
with diabetes mellitus receiving therapy who had a serum
creatinine level 1.0 mg/dL and no clinical evidence of other
microvascular disease, such as retinopathy or neuropathy.
Group 3 (n 21) were patients with ESRD diagnosed with
diabetic nephropathy by a nephrologist. Patients in groups 1
and 2 underwent catheterization for evaluation of chest pain.
Patients in group 3 had no symptoms and were obtained
from a group of 98 patients who were referred for catheterization for preoperative evaluation before renal transplantation, as per our protocol.10 Of these 98 patients, 63 were not
eligible for the study (47 had severe CAD, 6 had reduced
ventricular function), and 24 either refused to participate or

were not approached for the study. Clinical data were prospectively collected. Hyperlipidemia was defined as an lowdensity lipoprotein cholesterol level 130 mg/dL or treatment with a lipid-lowering agent. Patients were designated as
having hypertension when they were receiving drug treatment for hypertension, and patients were classified as having
diabetes mellitus when they were receiving pharmacologic
therapy (oral agents or insulin). The presence of coronary
disease in other arteries included only patients with noncritical (50%) stenosis. The presence of left ventricular hypertrophy (LVH) was defined with electrocardiographic criteria.11

Measurement of CFR
After the completion of the diagnostic catheterization, assessment of CFR was performed with methodology previously well described.12 In brief, a 0.014-inch Doppler ultrasound scanning Flowire (Cardiometrics, Mountain View,
Calif) was placed in an angiographically normal coronary,
with preference given to the left anterior descending artery
(78% of patients). Once satisfactory Doppler ultrasound scanning signals were obtained, the average peak velocity (APV)
was recorded at baseline along with the heart rate and blood
pressure. With a large-bore (6F or 7F) intravenous line in the
femoral vein, adenosine (140 ug/kg/min) was infused for 4
minutes to obtain maximal coronary hyperemia.13,14 Heart
rate, arterial pressure, and APV were again recorded at peak
hyperemia. CFR was calculated as the ratio of APV at peak
hyperemia to APV at rest. CFR 2.0 was defined as abnormal.

Statistical analysis
Data were analyzed with RS/1 software (RS/1 version 6.0.1,
copyright 1999, Domain Manufacturing Corporation, Burlington, Mass). All normally distributed data were expressed as
the mean plus or minus 1 SD; data not normally distributed
were expressed as the median (25th, 75th percentiles). Comparisons between groups were performed, and group differences of continuous variables were compared with Wilcoxon
signed rank tests. Group differences of categorical variables
were compared with 2 tests or, in the cases of small cell
sizes, the Fisher exact test. All P values are from 2-sided
tests. The hemodynamic variables were compared with analysis of variance. A multivariate predictive model using an ordinary least squares regression was performed to determine
independent predictors of flow reserve by controlling for potential confounding variables. The predictive probability for
CFR as a continuous variable and using the cutoff value of
2.0 was determined.

Results
Clinical characteristics
Clinical characteristics are shown in Table I. There
was no difference in the age, proportion of men, or
the prevalence of hyperlipidemia in the 3 groups. The
hematocrit level was lower in patients with diabetes
who had renal failure than in the other groups. There
was a higher proportion of patients with noncritical
disease in other arteries in the nondiabetic group and

American Heart Journal

Volume 147, Number 6

in the diabetic without renal failure group, as compared with the diabetic with renal failure group. The
incidence of both hypertension and the presence of
left ventricular hypertrophy (LVH) on electrocardiogram was greater in patients with diabetes mellitus
who had renal failure. Among the patients with diabetes mellitus, 86% of those with renal failure were
treated with insulin, as compared with only 20% of
those without renal failure. All 21 patients with diabetes and renal failure had retinopathy, and all but 6 had
neuropathy.

Systemic and coronary hemodynamics

At baseline, the systolic and mean blood pressures
and heart rate were higher in patients with diabetes
who had renal failure than in the other groups. The
diastolic blood pressures were not different between
groups. The baseline APV was higher in patients with
diabetes mellitus who had renal failure than in other
groups (Table II, Figure 1).
For the entire cohort, adenosine decreased both systolic (137 31 mm Hg at baseline vs 123 24 mm
Hg at peak hyperemia, P .001), diastolic (79 14
mm Hg at baseline vs 71 13 mm Hg at peak hyperemia, P .001), and mean blood pressure (103 20
mm Hg at baseline vs 93 16 mm Hg at peak hyperemia, P .001) . Similarly, adenosine increased heart
rate (74 12 beats/min at baseline vs 83 12 beats/
min at peak hyperemia, P .001).
At peak hyperemia, there were no significant differences in the groups in systolic, diastolic, or mean
blood pressures or in heart rate. APV increased in all 3
groups from baseline (Figure 1), with no difference
between groups. CVR is shown for each of the groups
in Figure 2. The mean CVR for patients without diabetes mellitus was 2.8 0.8 and was not different from
that of patients with diabetes mellitus who did not
have renal failure (2.7 0.7). Conversely, the mean
CVR for patients with diabetes mellitus who had renal
failure was 1.6 0.5 and was significantly lower than
that of both patients without diabetes mellitus and patients with diabetes mellitus who did not have renal
failure (P .001). As illustrated in Figure 1, C, the abnormal flow reserve observed in patients with diabetes
mellitus who had renal failure is caused primarily by a
higher APV at baseline (APV 35 cm/s in 8/12 patients or 67%) rather than an inability to reach the
same APV at peak hyperemia seen in the other groups.
An abnormal CVR, defined as CVR 2.0, was observed
in 3 of the 32 patients without diabetes mellitus (9%),
2 of the 11 patients with diabetes mellitus who did
not have renal failure (18%), and 12 of the 21 patients
with diabetes mellitus who had renal failure (57%).
The univariate predictors of an abnormal CVR, defined as a CVR 2.0, are summarized in Table III.
There was no difference in coronary vessel analyzed,

Ragosta et al 1019

Table II. Hemodynamics

Group 1,
Group 2,
Group 3,
nondiabetic DM no RF DM with RF
Baseline
SBP (mm Hg)
DBP (mm Hg)
Mean (mm Hg)
HR (beats/min)
APV (cm/s)
Hyperemia
SBP (mm Hg)
DBP (mm Hg)
Mean (mm Hg)
HR (beats/min)
APV (cm/s)

130 25
78 12
100 17
69 9
20 7

122 28
77 13
95 19
76 13
20 9

158 33
80 17
112 23
81 11
37 17

.001
.78
.03
.001
.001

123 22
74 12
94 15
80 12
54 14

111 24
71 13
87 18
85 9
51 19

130 24
69 15
94 18
86 13
52 14

.09
.44
.42
.17
.88

SBP, Systolic blood pressure, DBP, diastolic blood pressure, HR, heart rate, APV,
averaged peak velocity.

history of hypertension or hyperlipidemia, hematocrit

level, or the presence of coronary disease in other arteries between patients with CVR 2.0 and patients
with CVR 2.0. There was a higher incidence of LVH
in patients with CVR 2.0 than in patients with a normal CVR. Both the systolic blood pressure and heart
rate at baseline were higher in patients with a CVR
2.0 than in patients with a CVR 2.0. The presence
of diabetes mellitus and the presence of renal failure
were univariate predictors of an abnormal CVR.
To exclude the potentially confounding interaction
between LVH and renal failure on CVR, the analysis
was performed excluding the 10 patients with LVH, 9
of whom were in the diabetic with renal failure group
and 1 of whom was in the nondiabetic group. The
APV at baseline was higher in patients with diabetes
mellitus who had renal failure (20.6 6.8 cm/s for
the nondiabetic group, 20.3 8.5 for the diabetic
without renal failure group, and 32.0 15.8 cm/s for
the diabetic with renal failure group; P .003). The
APV at peak hyperemia was the same in the 3 groups
(53.4 13.7 cm/s for the nondiabetic group, 51.3
18.5 for the diabetic without renal failure group, and
52.0 15.2 cm/s for the diabetic with renal failure
froup; P .91). Thus, CVR was lower in the diabetic
with renal failure group than in the other 2 groups
(CVR: 2.8 0.8 for the nondiabetic group, 2.7 0.7
for the diabetic without renal failure group, and 1.8
0.6 for the diabetic with renal failure group; P .001).
To determine the independent predictors of CVR
both as a continuous variable and using the cutoff of
2.0, a multivariate predictive model with ordinary
least squares regression was created. The variables entered into the model included the presence of LVH,
systolic blood pressure, heart rate, the presence of coronary disease in other vessels, and patient group.

American Heart Journal

June 2004

1020 Ragosta et al

Figure 1

Figure 2

CVR in the 3 patient groups. DM, Diabetes mellitus; RF, renal

failure.

Table III. Univariate predictors of coronary velocity reserve

2.0

Vessel (# LAD)
HTN
Hyperlipidemia
Hematocrit (%)
Other CAD
LVH
Baseline HR (beats/min)
Baseline SBP (mm Hg)
Diabetes
Renal failure

CVR
>2.0
(n 47)

CVR
<2.0
(n 17)

36
31
37
38 5
31
3
72 10
133 26
18
9

14
11
11
36 6
7
7
81 13
152 40
14
12

.74
1.0
.33
.2
.09
.002
.004
.02
.004
.001

CVR, Coronary velocity reserve; LAD, left anterior descending artery.

APV at baseline and peak hyperemia in patients without diabetes

mellitus (A), patients with diabetes mellitus who do not have renal
failure (B), and patients with diabetes mellitus who do have renal
failure (C).

On the basis of this predictive model, coefficients

and 95% CIs predicting the change in CVR as a continuous variable were determined. The results of this
analysis are shown in Table IV. These data demonstrate that when other variables are controlled, patients with LVH are predicted to have a CVR that is
0.11 units less than patients without hypertrophy. This
difference was not significant. Similarly, there was no
difference in the predicted CVR between patients with
and patients without coronary artery disease in other
vessels. When other variables are controlled, the predicted CVR did not vary significantly with the systolic
pressure, but did depend on the heart rate. The predicted CVR was the same in both patients without diabetes mellitus and patients with diabetes mellitus who
did not have renal failure; however, patients with diabetes mellitus who had renal failure were predicted to
have a CVR that was 0.87 units less than that of pa-

American Heart Journal

Volume 147, Number 6

Ragosta et al 1021

Table IV. Multivariate predictors of coronary velocity reserve

as a continuous variable
Variable
No LVH vs LVH
No other CAD vs other CAD
Baseline SBP*
Baseline HR*
Non-DM vs DM no RF
Non-DM vs DM with RF
DM no RF vs DM with RF

Figure 3

Coefficient (95% CI)

0.11 (0.66, 0.45)

0.045 (0.40, 0.31)
0.0029 (0.0090, 0.0032)
0.022 (0.038, 0.0055)
0.051 (0.43, 0.53)
0.87 (1.37, 0.37)
0.92 (1.51, 0.33)

.71
.80
.36
.01
.83
.001
.004

*For the continuous variables, represents the amount of change of coronary velocity reserve for a one unit change in the continuous variable. For example, patients
with heart rate of 70 are predicted to have a coronary velocity reserve of 0.22
units lower than patients with heart rate of 60.

tients without diabetes mellitus. This difference was

highly significant. Similarly, patients with diabetes mellitus who had renal failure were predicted to have a
coronary velocity reserve that was 0.92 units less than
that of patients with diabetes mellitus who did not
ahve renal failure.
Similar findings were observed when the model was
used to predict the probability of CFR 2.0. The results of this analysis are shown in Figure 3. Patients
without diabetes mellitus who did not have LVH had a
36% probability of having abnormal CFR after all other
variables are adjusted. Patients with diabetes mellitus
who did not have renal failure had a predicted probability similar to that of patients without diabetes mellitus. However, patients with diabetes mellitus who had
renal failure had an 84% probability of having an abnormal CVR. A similar probability of having an abnormal CFR was seen with and without the presence of
LVH, with and without coronary disease in other vessels, and at 3 levels of systolic pressure (on the basis
of the median and 25th and 75th percentiles). Patients
with a heart rate greater than 83 beats/min had a
greater probability of an abnormal CFR than patients
with lesser heart rates that were not different than
normal.

Discussion
In this study, diminished CVR was observed in
asymptomatic patients with diabetes mellitus who had
nephropathy and an angiographically normal coronary
artery. Patients with diabetes mellitus who did not
have renal failure had a CVR similar to that of patients
without diabetes mellitus. With multivariable analysis,
diabetes with renal failure was independently associated with the presence of abnormal CVR. These data
suggest that in the absence of end-organ damage, diabetes mellitus alone does not adversely affect CVR.
However, when significant end-organ complications of

Predicted probabilities with 95% CIs for having a CVR 2.0.

CAD, Coronary artery disease; HR, heart rate in beats/min; SBP,
systolic blood pressure in mm Hg.

diabetes mellitus are present, coronary reserve may

also be abnormal.
Our results shed some light on the mechanism of
impaired flow reserve in patients with diabetes mellitus who have renal failure. If a reduction in CFR was
caused by microvascular disease in the heart, then the
APV at baseline would be expected to be low and
would fail to increase after administration of a vasodilator compared with healthy patients. In this study, impaired flow reserve in patients with diabetes mellitus
who had renal failure was caused primarily by an elevation of the baseline APV (8/12 patients or 67%) and
not by diminished hyperemic APV (4/12 patients or
33%). This abnormality has also been reported in patients with diabetes mellitus who have retinopathy7
and in heart transplant recipients.15 Furthermore,
these findings argue against a reduction in CFR from
diffuse atherosclerosis, which would also result in an
attenuation of the APV at peak hyperemia16 and not an
elevated baseline velocity. The elevated baseline velocities may be caused by an increase in left ventricular
mass from long-standing hypertension, which is common in this population, or by circulating humoral factors with vasodilator properties present in renal failure. Increased levels of both nitric oxide and
endothelin have been measured in patients with
ESRD.1719 Although patients with ESRD often have
anemia, which may in part explain these results, hematocrit levels correlated poorly with baseline APV (r
0.26) and were not statistically different in patients with abnormal CVR versus patients wtih normal
CVR.

American Heart Journal

June 2004

1022 Ragosta et al

Several other studies have found abnormal flow reserve in patients with diabetes mellitus. Nahser et al
found lower CVR in patients with diabetes mellitus
who had angiographically normal coronary arteries, as
compared with patients without diabetes mellitus, and
found no association with hypertension.6 The average
peak velocity data were not presented to determine
whether the abnormality was caused by elevated baseline velocities, as observed in our study, or from blunting of the hyperemic response suggesting microvascular disease. Other studies showing reduced flow
reserve in patients with diabetes mellitus did not include angiography and thus did not exclude atherosclerosis as the explanation for abnormal flow reserve.20,21 Only 1 study, an investigation using
thermodilution technique to measure CFR, determined
that flow reserve in patients with diabetes mellitus was
abnormal because of an inability to achieve the same
hyperemic flow as that in patients without diabetes
mellitus, which suggested microvascular disease.5
Akasaka and colleagues studied patients with diabetes
mellitus who had retinopathy and found results very
similar to ours.7 Similar to our results, in that study,
patients with diabetes mellitus who had retinopathy
had impairment of CFR caused by an elevated baseline
APV. Patients with diabetes mellitus who did not have
retinopathy had flow velocities and flow reserve similar to that of patients without diabetes mellitus.

Limitations
There are several important limitations of this study.
We selected patients with angiographically normal coronary arteries; however, diffuse atherosclerosis not
appreciated with angiography might be responsible for
the impaired flow reserve. This is unlikely because the
mechanism of abnormal flow reserve in this study was
primarily from elevation of the baseline APV and not a
reduction in hyperemic flow.16 Selection bias may play
a role because the indication for catheterization was
different for each group. Furthermore, the close association among hypertension, LVH, and renal failure
makes it difficult to dissociate the effects of LVH from
end-organ damage from diabetes mellitus, and we did
not have a group of patients with ESRD who did not
have diabetes mellitus. Ventricular hypertrophy alone
may cause abnormal flow reserve and might account
for some of the abnormalities observed in this
study.20 26 We used electrocardiography to diagnose
LVH and did not find this to be a predictor of abnormal CVR. Our results might have been different had
we used echocardiography to diagnose LVH. Another
important consideration is that patients with diabetes
mellitus who had renal failure had a higher proportion
of insulin-requiring diabetes mellitus than patients with
diabetes mellitus who did not have renal failure. Insulin has effects on vascular reactivity, and insulin resis-

tance is associated with impaired vascular reactivity.27

Whether insulin use is important in determining CFR is
not known. Finally, we used intravenous adenosine,
which has been previously shown to induce maximal
hyperemia.13,14 Whether the same results would have
been obtained with other vasodilators or routes of administration is not known.

Clinical implications
Diabetes mellitus has been associated with angina
and heart failure in patients with normal coronaries.
The presence of abnormal flow reserve in patients
with diabetes mellitus and ESRD suggests a possible
mechanism for these conditions and for the excessive
cardiovascular mortality rate seen in these patients.1 4
Although atherosclerotic disease is well known to accelerate in renal failure,28 30 these data suggest that
abnormalities in flow reserve are also present. Furthermore, the noninvasive examination of patients with
ESRD, typically done as a prelude to renal transplantation, has been problematic. Some investigators have
found very poor sensitivity rates (37%53%) and specificity rates (73% 63%) for identifying patients with
50% coronary stenosis.3133 Our data suggests that
the poor sensitivity and specificity rates may relate to
the high frequency of impaired flow reserve in this
population. Vasodilator stress perfusion imaging relies
on the relative reduction of flow reserve in the vascular bed subtended by a stenosed artery compared with
the vascular bed of a normal artery. In patients with
diabetes mellitus who have ESRD, vasodilator stress
perfusion imaging might be unreliable because flow
reserve in the bed subtended by the normal artery may
also be abnormal.

Conclusion
Diabetic nephropathy with ESRD is associated with
diminished CFR, whereas patients with diabetes mellitus who do not have ESRD have a CFR similar to that
of patients without diabetes mellitus. Thus, in the
presence of end-organ damage caused by diabetes mellitus, abnormalities in coronary physiology may be
seen in the absence of overt epicardial coronary artery
disease.

References
1. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal failure. Am J Kidney Dis 1998;
32(3 Suppl):S1129.
2. Hypolite IO, Bucci J, Hshieh P, et al. Acute coronary syndromes
after renal transplantation in patients with end-stage renal disease
resulting from diabetes. Am J Transplantation 2002;2:274 81.
3. Aakhus S, Dahl K, Wideroe TE. Cardiovascular morbidity and risk
factors in renal transplant patients. Nephrol Dial Transplant 1999;
14:648 54.

American Heart Journal

Volume 147, Number 6

4. Lin K, Stewart D, Cooper S, et al. Pre-transplant cardiac testing for

kidney-pancreas transplant candidates and association with cardiac outcomes. Clin Transplantation 2001;15:269 75.
5. Strauer BE, Motz W, Vogt M, et al. Evidence for reduced coronary
flow reserve in patients with insulin-dependent diabetes: a possible
cause for diabetic heart disease in man. Exp Clin Endocrinol Diabetes 1997;105:1520.
6. Nahser PJ, Brown RE, Oskarsson H, et al. Maximal coronary flow
reserve and metabolic coronary vasodilation in patients with diabetes mellitus. Circulation 1995;91:635 40.
7. Akasaka T, Yoshida K, Hozumi T, et al. Retinopathy identifies
marked restriction of coronary flow reserve in patients with diabetes mellitus. J Am Coll Cardiol 1997;30:935 41.
8. Fioretto P, Mauer M, Brocco E, et al. Patterns of renal injury in
NIDDM patients with microalbuminuria. Diabetologia 1996;39:
1569 76.
9. Mauer SM, Lane P, Hattori M, et al. Renal structure and function in
insulin-dependent mellitus and type I membranoproliferative
glomerolunephritis in humans. J Am Soc Nephrol 1992;2(10
Suppl):S181 4.
10. Manske CL, Thomas W, Wang Y, et al. Screening diabetic transplant candidates for coronary artery disease: identification of a
low risk subgroup. Kidney Int 1993;44:61721.
11. Romhilt DW, Bove KE, Norris RJ, et al. A critical appraisal of the
electrocardiographic criteria for the diagnosis of left ventricular
hypertrophy. Circulation 1969;40:18595.
12. Kern MJ, Meier B. Evaluation of the culprit plaque and the physiologic significance of coronary atherosclerotic narrowings. Circulation 2001;103:31429.
13. Wilson RF, Wyche K, Christensen BV, et al. Effects of adenosine
on human coronary arterial circulation. Circulation 1990;82:
1595 606.
14. Kern MJ, Deligonul E, Tatineni S, et al. Intravenous adenosine:
continuous infusion and low dose bolus administration for determination of coronary vasodilator reserve in patients with and without
coronary artery disease. J Am Coll Cardiol 1991;18:718 29.
15. Volker K, Spes CH, Rieber J, et al. Predictors of reduced coronary
flow reserve in heart transplant recipients without angiographically
significant coronary artery disease. Transplantation 1999;68:
1477 81.
16. Uren NG, Melin JA, De Bruyne B, et al. Relation between myocardial blood flow and the severity of coronary-artery stenosis. New
Engl J Med 1994;330:1782 8.
17. Raj DS, Vincent B, Simpson K, et al. Hemodynamic changes during hemodialysis: role of nitric oxide and endothelin. Kidney Int
2002;61:697704.
18. Rysz J, Luciak M, Kedziora J, et al. Nitric oxide release in the peripheral blood during hemodialysis. Kidney Int 1997;51:294
300.
19. Roccatello D, Mengozzi G, Alfieri V, et al. Early increase in blood
nitric oxide, detected by electron paramagnetic resonance as ni-

Ragosta et al 1023

20.

21.
22.

23.

24.

25.

26.

27.
28.

29.

30.

31.

32.

33.

trosylhaemoglobin, in haemodialysis. Nephrol Dial Transplant

1997;12:2927.
Yokoyama I, Momomura SI, Ohtake T, et al. Reduced myocardial
flow reserve in non-insulin dependent diabetes mellitus. J Am Coll
Cardiol 1997;30:14727.
Pitkanen OP, Nuutila P, Raitakari OT, et al. Coronary flow reserve
is reduced in young men with IDDM. Diabetes 1998;47:248 54.
Houghton JL, Carr AA, Prisant LM, et al. Morphologic, hemodynamic and coronary perfusion characteristics in severe left ventricular hypertrophy secondary to systemic hypertension and evidence
of nonatherosclerotic myocardial ischemia. Am J Cardiol 1992;
69:219 24.
Houghton JL, Frank MJ, Carr AA, et al. Relations among impaired
coronary flow reserve, left ventricular hypertrophy and thallium
perfusion defects in hypertensive patients without obstructive coronary artery disease. J Am Coll Cardiol 1990;15:4351.
Anderson HV, Stokes MJ, Leon M, et al. Coronary artery flow velocity is related to lumen area and regional left ventricular mass.
Circulation 2000;102:48 54.
Hamasaki S, Al Suwaidi J, Higano ST, et al. Attenuated coronary
flow reserve and vascular remodeling in patients with hypertension
and left ventricular hypertrophy. J Am Coll Cardiol 2000;35:
1654 60.
Laine H, Raitakari OT, Niinikoski H, et al. Early impairment of
coronary flow reserve in young men with borderline hypertension.
J Am Coll Cardiol 1998;32:14753.
Baron AD. Vascular reactivity. Am J Cardiol 1999;84(1 Suppl):
257.
Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000;342:1478 83.
Oh J, Wunsch R, Turzer M, et al. Advanced coronary and carotid
arteriopathy in young adults with childhood-onset chronic renal
failure. Circulation 2002;106:100 5.
Gradeaus F, Ivens K, Peters AJ, et al. Angiographic progression of
coronary artery disease in patients with end-stage renal disease.
Nephrol Dial Transplant 2001;16:1198 202.
Marwick T, Steinmuller DR, Underwood DA, et al. Ineffectiveness
of dipyridamole SPECT Thallium imaging as a screening technique
for coronary artery disease in patients with end-stage renal failure. Transplantation 1990;49:100 3.
Brown JH, Vites NP, Testa HJ, et al. Value of thallium myocardial
imaging in the prediction of future cardiovascular events in patients with end-stage renal failure. Nephrol Dial Transplant 1993;
8:4337.
Vandenberg B, Rossen JD, Grover-Mckay M, et al. Evaluation of
diabetic patients for renal and pancreas transplantation: non-invasive screening for coronary artery disease using radionuclide
methods. Transplantation 1996;62:1230 5.

Reproduced with permission of the copyright owner. Further reproduction prohibited without
permission.